Project Summary/Abstract The vascular access is the ?Achilles Heel? of the hemodialysis procedure. Sixty percent of arteriovenous fistulas (AVF) that are created fail to mature successfully for dialysis use (AVF non-maturation), resulting in a very significant clinical morbidity and mortality for hemodialysis patients. On a radiologic level, AVF non- maturation is most commonly characterized by a juxta-anastomotic stenosis, and at a histological level it is characterized by a combination of aggressive neointimal hyperplasia at the juxta-anastomosis and an absence of outward vascular remodeling. At present, there remains a fundamental gap in our understanding of the mechanisms and pathways that lead to AVF non-maturation. Thus, there are few, if any, effective therapies to improve AVF non-maturation. The poor early outcomes following AVF creation and lack of therapies to treat this clinical problem represent an unmet clinical need. Our long-term goal is to better understand the pathobiology of AVF non-maturation in order to develop novel therapies. Preliminary work from our rodent AVF model has shown impaired endothelial-dependent vasorelaxation (EDR) locally at the AVF early after creation. Impairment in EDR represents reduced endothelial nitric oxide synthase (NOS3)-derived nitric oxide (NO) bioavailability. A decrease in NO bioavailability is associated with endothelial dysfunction. NOS3 and cGMP regulation play key roles in regulating nitric oxide (NO) bioavailability and vascular endothelial function. We have identified histone deacetylase-1 (HDAC-1), through its dysregulation of NOS3 function, and cyclic guanosine monophosphate (cGMP) as potential mediators of endothelial dysfunction following AVF creation. Thus, the objective of this proposal is to examine two important systems, HDAC1 and cGMP, that may play key roles in influencing endothelial function during AVF development. The central hypothesis of this proposal is that dysregulation of NOS3 and cGMP activity during AVF development (exacerbated in the setting of chronic kidney disease), results in loss of NO bioavailability, which impacts AVF remodeling and neointimal hyperplasia development. We will test our central hypothesis with two specific aims: (1) To evaluate mechanisms by which HDAC1 reduces NOS3 function and alters local endothelial function in the setting of AVF development and (2)To determine the effects of inhibiting cGMP degradation on restoring local endothelial function, and improving AVF remodeling and reducing neointimal hyperplasia development. We believe our proposed research is significant because it is expected to advance the understanding of the pathobiology of AVF non-maturation. Ultimately, such knowledge has the potential to improve therapies for AVF non-maturation. We expect that novel therapies to treat AVF non-maturation will positively impact Veteran ESRD patients' health by improving morbidity and mortality, through reduction in tunneled hemodialysis catheter use.